Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease [Oligodendrocytes LCM data]. Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease [Oligodendrocytes LCM data]

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type. We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for β-amyloid related functional classes, including the known Alzheimer’s disease (AD) genes, APP and PSEN1. This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases. Overall design: RNA sequencing case-control study between MSA patients and controls (Oligodendrocytes LCM data)

多系统萎缩（Multiple System Atrophy, MSA）是一种病因不明的罕见成年起病神经退行性疾病，目前尚无有效治疗方案，亦无法治愈。迄今为止，针对该疾病相关转录组变化的研究仍较为有限，其临床表现可分为以帕金森综合征为主型（MSA-P）和小脑型（MSA-C，原文笔误为MSC-C）两类。
本研究报道了两个独立队列的多系统萎缩患者（n=66）与健康对照（Healthy Controls, HC；n=66）的小脑白质（Cerebellar White Matter, CWM）组织的RNA表达谱分析结果。研究对大块脑组织及通过激光捕获显微切割（Laser Capture Microdissection, LCM）获取的少突胶质细胞的RNA样本进行了测序，筛选得到差异表达基因（Differentially Expressed Genes, DEGs），并在按MSA临床亚型分层前后分别对其进行了分析。
结果显示，MSA-C组的差异表达基因数量最多（n=747），而MSA-P组仅检出1个差异表达基因，这表明MSA-C型小脑白质的转录组失调程度更为显著。大块脑组织与LCM分析的结果均显示，少突胶质细胞相关基因表达下调，且髓鞘形成过程显著富集，其中QKI基因发挥了关键调控作用。此外，本研究观察到MSA-C组神经元特异性基因表达显著上调，突触相关过程显著富集。第三类基因与星形胶质细胞和内皮细胞基因的上调相关，这两种细胞类型在炎症过程中均具有关键作用。最后，针对MSA-C的网络分析显示，其显著富集β淀粉样蛋白相关功能类别，包括已知的阿尔茨海默病（Alzheimer’s Disease, AD）相关基因APP与PSEN1。
本研究是迄今为止针对多系统萎缩患者死后脑组织开展的规模最大的RNA谱分析研究。本研究明确了MSA-C型特异性的基因表达特征，揭示了该疾病复杂神经退行性级联反应的不同阶段，其中包括多种细胞特异性转录程序的改变。此外，多项结果提示，尽管多系统萎缩与阿尔茨海默病在临床及神经病理特征上存在显著差异，但二者存在共同的转录失调现象。
总体设计：多系统萎缩患者与健康对照之间的RNA测序病例对照研究（包含少突胶质细胞LCM数据）